Freeze-dried pantoprazole preparation and pantoprazole injection

ABSTRACT

Lyophilized pantoprazole preparations which are obtainable by freeze-drying of an aqueous solution of pantoprazole, ethylenediamine tetraacetic acid and/or a suitable salt thereof, and sodium hydroxide and/or sodium carbonate are disclosed. The preparations have advantageous properties when reconstituted for injection.

This application is a Continuation of USSN 10/195,062, filed Jul. 15,2002, now U.S. Pat. No. 6,780,831, which is a Continuation-In-Part (CIP)of International Patent Application No. PCT/EP01/13296 filed Nov. 17,2001.

TECHNICAL FIELD

The present invention relates to the field of pharmaceutical technologyand describes freeze-dried5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazolepreparations and a5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazoleinjection. Furthermore the invention also relates to a process for theproduction of freeze-dried5-difluoromethoxy-2-[(3,4dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazoleand a5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazoleinjection.

PRIOR ART

WO94/02141 describes an injection comprising a2-[(2-pyridyl)methylsulfinyl]-benzimidazole compound an aqueous solventadded with no nonaqueous solvent, wherein the pH of the injection is notless than 9.5 and not more than 11.5. It is mentioned that saidinjection does not cause hemolysis and causes less local irritation.

DE 43 24 014 describes the preparation of a lyophilisate ofpantoprazole-sodium sesquihydrate in the presence of sucrose as anauxiliary at production temperatures of −25 to −30° C. It is disclosedthat the lyophilisate is of improved storage stability and can be storedat room temperature for at least 18 months and is easily reconstitutedin liquid form in suitable doses for use.

CN 1235018 describes a freeze-dried injection powder of pantoprazolesodium containing no crystallised water with pH value of 9-12.5, whichis composed of pantoprazole sodium, freeze-dried powder supportingagent, metal ion complexing agent and pH regulator.

WO99/18959 describes aqueous pharmaceutical compositions which arechemically and physically stable for intravenous injection whichcomprise anti-ulcerative compound and glycine as stabilizer in carrier.

DESCRIPTION OF INVENTION

Reconstitution of lyophilised pharmaceutical compounds with carriersolutions for application may lead to the formation of visible and/orsubvisible particles in the solution. Injectable solutions, includingsolutions constituted from sterile solids intended for parenteral useshould be essentially free from particles that can be observed on visualinspection and for patient safety it is also desirable to have a lownumber of subvisible particles. USP (United States Pharmacopeia) 24describes physical tests performed for the purpose of enumeratingsubvisible extraneous particles within specific size ranges and alsodefines particulate matters limits set forth for the test being appliedfor large-volume injections for single-dose infusion and small-volumeinjections (USP 24, <788> Particulate Matter in injections).

Surprisingly it has now been found that by freeze drying of an aqueoussolution of pantoprazole, ethyl-enediamine tetraacetic acid and/or asuitable salt thereof, and sodium hydroxide and/or sodium carbonate alyophilisate is obtained having significantly lower number of subvisibleparticles after reconstitution with a solvent compared to lyophilisatesof the state of the art. The lyophilisate according to the invention isvery stabile and is easily reconstituted with suitable solvents. Inparticular the pantoprazole injection according to the invention hasless than 130, preferably less than 120 subvisible particles/per vial,the particles having a size equal to or greater as 10 μm, the number ofparticles determined according to USP 24 (<788> Particle Matter ininjections) by light obscuration particle test count.

5-Difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: pantoprazole, in connection with the invention also referred to aspantoprazole) is known from EP-A-0 166 287. Pantoprazole is a chiralcompound. In connection with the invention the term pantoprazole alsoincludes the pure enantiomers of pantoprazole and their mixtures in anymixing ratio. (S)-pantoprazole [(−)-pantoprazole] may be mentioned byway of example. Pantoprazole is present here as such or preferably inthe form of it's salt with a base. Examples of salts with a base whichmay be mentioned are sodium, potassium, magnesium and calcium salts.Pantoprazole and/or a salt thereof may contain various amounts ofsolvent when isolated in crystalline form. In connection with theinvention pantoprazole also refers to all solvates and in particular tohydrates of 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole and salts thereof. Such a hydrate ofthe salt of pantoprazole with a base is disclosed, for example, inWO91/19710. Expediently pantoprazole refers to pantoprazole sodiumsesquihydrate (=pantoprazole sodium×1.5H₂O) and pantoprazole magnesiumdihydrate.

According to the, invention the pantoprazole solution used in the freezedrying process can be obtained by addition of ethylenediaminetetraacetic acid and/or a suitable salt thereof, and sodium hydroxideand/or sodium carbonate to an aqueous solvent. Suitable salts ofethylenediamine tetraacetic acid which may be mentioned in connectionwith the invention by way of example are ethylenediamine tetraaceticacid disodium salt, ethylenediamine tetraacetic acid calcium disodiumsalt ethylenediamine tetraacetic acid trisodium salt and ethylenediaminetetraacetic acid tetrasodium salt. The proportion by weight ofethylenediamine tetraacetic acid and/or a suitable salt thereof, basedon the amount of pantoprazole used is from 0.05 to 25% preferably from0.25 to 12.5% or particular preferred from 1 to 5%. The aqueous solventpreferentially is water for injection. Subsequently pantoprazole isadded to the solution and dissolved by stirring. It is preferred to havea solution wherein the proportion of weight (m/m) of pantoprazole is 0.5to 10%, particularly preferred 1 to 6%. In a further preferredembodiment of the invention the pH of the solution used in the freezedrying process is 8 or above 8. Particularly preferred the pH of saidsolution is in the range from 10 to 13, more preferred the pH of thesolution is in the range from 10.5 to 11.5 and particularly morepreferred the pH is in the range from 10.75 to 11.25. Exemplary pHvalues of said solution, which are to be emphasized are 10.75, 10.8,10.85, 10.9, 10.95, 11, 11.05, 11.1, 11.15, 11.2 and 11.25. Then thissolution is filtered for sterilization and charged in vials. Thesolution is then freeze dried by a method known per se.

A pantoprazole injection according to the invention can be produced bydissolving the lyophilized product thus obtained in a suitable solventfor example physiological saline, aqueous solution of 5% glucose, ordistilled water for injection. Preferably the pantoprazole injectionaccording to the invention is used in the form of intravenous injection.

The lyophilised product and pantoprazole injection according to theinvention preferably contain pantoprazole in the dose customary for thetreatment of the respective disease. The lyophilised product andpantoprazole injection according to the invention can be employed forthe treatment and prevention of all the diseases which are regarded astreatable or avoidable by the use ofpyridin-2-ylmethylsulfinyl-1H-benzimidazoles. In particular, thelyophilised product and pantoprazole injection according to theinvention can be employed in the treatment of stomach disorders. Thelyophilized products in particular contain between 5 and 150 mg,preferably between 5 and 60 mg, of pantoprazole. Examples which may bementioned are lyophilized products or injections which contain 10, 20,40, 50 or 96 mg of pantoprazole. The administration of the daily dose(e.g. 40 mg of active compound) can be carried out, for example, in theform of an individual dose or by means of a number of doses of theadministration forms according to the invention (e.g. 2 times 20 mg ofactive compound). The concentration of pantoprazole in the injectionaccording to the invention may vary depending upon the administrationroute and generally ranges in a proportion of 0.05-10 mg/ml, preferably0.1 to 5 mg/ml on a free compound basis. For example for bolusadministration 20 to 120 mg of lyophilized product according to theinvention can be reconstituted with 10 ml physiological saline.

The production of the lyophilized product and pantoprazole injection isdescribed by way of example below. The following examples illustrate theinvention in greater detail, without restricting it.

EXAMPLES Production of a Lyophilized Pantoprazole Preparation Example 1

Under nitrogen atmosphere, 0.276 g Ethylenediamine tetraacetic aciddisodium salt and 6.7 g sodium hydroxide (1N aqueous solution) are addedto 480 g water for injection of 4° C. To 8° C. 12.47 g pantoprazolesodium sesquihydrate is added while stirring to give a clear solution.The weight of the solution is adjusted to 500 g by addition of water forinjection. The pH of the solution is 11.76. The solution is filteredthrough a 0.2 μm membrane filter and filled in glass vials (1.81 g byvial). Filled vials are semi-stoppered and put into a freeze-dryer (GT4Edwards/Kniese or GT8 Amsco) for lyophilisation. The vials are cooled to−45° C., then the temperature is raised to −20 to −5° C. under vacuum(0.1 to 0.5 mbar) for drying. After finishing main drying thetemperature is raised to 30° C., the vacuum is adjusted to 0.01 mbar anddrying is continued for an additional 3 hours. An off-white lyophilizedproduct is obtained which is easily reconstituted with physiologicalsaline to give a clear solution.

Example 1a

Under nitrogen atmosphere, 0.276 g Ethylenediamine tetraacetic aciddisodium salt and 1.66 ml sodium hydroxide solution (1N aqueoussolution) are added to 480 g water for injection of 4° C. To 8° C. 12.47g pantoprazole sodium sesquihydrate is added while stirring to give aclear solution. The weight of the solution is adjusted to 500 g byaddition of water for injection. The pH of the solution is 11.76. Thesolution is filtered through a 0.2 μm membrane filter and filled inglass vials (1.81 g by vial). Filled vials are semi-stoppered and putinto a freeze-dryer (GT4 Edwards/Kniese or GT8 Amsco) forlyophilisation. The vials are cooled to −45° C. then the temperature israised to −20 to −5° C. under vacuum (0.1 to 0.5 mbar) for drying. Afterfinishing main drying the temperature is raised to 30° C., the vacuum isadjusted to 0.01 mbar and drying is continued for an additional 3 hours.An off-white lyophilized product is obtained which is easilyreconstituted with physiological saline to give a clear solution.

Comparative Examples Example 2

Under nitrogen atmosphere, 12.47 g pantoprazole sodium sesquihydrate isadded to 480 g water for injection of 4° C. To 8° C. while stirring togive a clear solution. The volume of the solution is adjusted to 500 gby addition of water for injection. The pH of the solution is 10.85. Thesolution is filtered through a 0.2 μm membrane filter and filled inglass vials (1.81 g by vial). Filled vials are semi-stoppered and putinto a freeze-dryer (GT4 Edwards/Kniese or GT8 Amsco) forlyophilisation. The vials are cooled to −45° C., then the temperature israised to −20 to −5° C. under vacuum (0.1 to 0.5 mbar) for drying. Afterfinishing main drying the temperature is raised to 30° C., the vacuum isadjusted to 0.01 mbar and drying is continued for an additional 3 hours.An off-white lyophilized product is obtained.

Example 3

Under nitrogen atmosphere, 2.45 g sodium hydroxide (1N aqueous solution)is added to 480 g water for injection of 4° C. To 8° C. 12.47 gpantoprazole sodium sesquihydrate is added while stirring to give aclear solution. The weight of the solution is adjusted to 500 g byaddition of water for injection. The pH of the solution is 12.02. Thesolution is filtered through a 0.2 μm membrane filter and filled inglass vials (1.81 g by vial). Filled vials are semi-stoppered and putinto a freeze-dryer (GT4 Edwards/Kniese or GT8 Amsco) forlyophilisation. The vials are cooled to −45° C., then the temperature israised to −20 to −5° C. under vacuum (0.1 to 0.5 mbar) for drying. Afterfinishing main drying the temperature is raised to 30° C., the vacuum isadjusted to 0.01 mbar and drying is continued for an additional 3 hours.An off-white lyophilized product is obtained.

Example 4

Under nitrogen atmosphere, 0.05 g Ethylenediamine tetraacetic aciddisodium salt is added to 480 g water for injection of 4° C. To 8° C.12.47 g pantoprazole sodium sesquihydrate is added while stirring togive a clear solution. The weight of the solution is adjusted to 500 gby addition of water for injection. The pH of the solution is 10.2. Thesolution is filtered through a 0.2 μm membrane filter and filled inglass vials (1.81 g by vial). Filled vials are semi-stoppered and putinto a freeze-dryer (GT4 Edwards/Kniese or GT8 Amsco) forlyophilisation. The vials are cooled to −45° C., then the temperature israised to −20 to −5° C. under vacuum (0.1 to 0.5 mbar) for drying. Afterfinishing main drying the temperature is raised to 30° C. the vacuum isadjusted to 0.01 mbar and drying is continued for an additional 3 hours.An off-white lyophilized product is obtained.

Light Obscuration Particle Test Count

Particulate matter/per vial in solutions constituted from thelyophilized products obtained according to Examples 1 to 4 weredetermined according to USP 24 (<788>Particulate Matter in injections)by light obscuration particle test count.

The number of extraneous particles per vial having a size equal to orgreater as 10 μm detected are summarized in Table 1. As may be evidentfrom table 1, the number of subvisible particles per vial (equal to orgreater as 10 μm) in solutions constituted from products obtainedaccording to the invention (EXAMPLE 1) is lower than for productsobtained by methods which differ from the present invention (EXAMPLES 2to 4).

TABLE 1 EXAMPLE 1 (Product obtained by EXAMPLE 4 freeze drying of Pan-(Product obtained by toprazole sodium EXAMPLE 3 freeze drying of Pan-sesquihydrate, so- EXAMPLE 2 (Product obtained by toprazole sodium diumhydroxide and (Product obtained by freeze drying of Pan- sesquihydrateand ethylenediamine freeze drying of Pan- toprazole sodiumethylenediamine tetraacetic acid diso- toprazole sodium sesquihydrateand tetraacetic acid diso- dium salt) sesquihydrate) sodium-hydroxide)dium salt) particles/per vial particles/per vial particles/per vialparticles/per vial > = 10 μm > = 10 μm > = 10 μm > = 10 μm 109 458 144211

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of thefollowing claims.

1. Lyophilized preparation consisting of: (a)5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(pantoprazole) or a solvate, hydrate, salt, hydrate of a salt or solvateof a salt thereof; (b) ethylenediamine tetraacetic acid and/or asuitable salt thereof, and (c) sodium hydroxide and/or sodium carbonate.2. The preparation according to claim 1, wherein the pantoprazole ispantoprazole sodium.
 3. The preparation according to claim 1, whereinthe pantoprazole is pantoprazole sodium sesquihydrate.
 4. Thepreparation according to claim 1, wherein the pantoprazole ispantoprazole magnesium.
 5. The preparation according to claim 1, whereinthe pantoprazole is pantoprazole magnesium dihydrate.
 6. The preparationaccording to claim 1, wherein the pantoprazole is (−)-pantoprazole or asolvate, hydrate, salt, hydrate of a salt or solvate of a salt thereof.7. The preparation according to claim 1, wherein the ethylenediaminetetraacetic acid is present as ethylenediamine tetraacetic acid disodiumsalt.
 8. The preparation according to claim 2, wherein theethylenediamine tetraacetic acid is present as ethylenediaminetetraacetic acid disodium salt.
 9. The preparation according to claim 3,wherein the ethylenediamine tetraacetic acid is present asethylenediamine tetraacetic acid disodium salt.
 10. The preparationaccording to claim 4, wherein the ethylenediamine tetraacetic acid ispresent as ethylenediamine tetraacetic acid disodium salt.
 11. Thepreparation according to claim 5, wherein the ethylenediaminetetraacetic acid is present as ethylenediamine tetraacetic acid disodiumsalt.
 12. The preparation according to claim 6, wherein theethylenediamine tetraacetic acid is present as ethylenediaminetetraacetic acid disodium salt.
 13. The preparation according to claim1, consisting of (a) Pantoprazole sodium; (b) ethylenediaminetetraacetic acid disodium salt; and (c) sodium hydroxide.
 14. Thepreparation according to claim 1 consisting of: (a) Pantoprazole sodiumsesquihydrate; (b) ethylenediamine tetraacetic acid disodium salt; and(c) sodium hydroxide.